Preparation of pyrazolines by cyclization of an azine

ABSTRACT

Alkyl substituted pyrroles and pyrazolines are prepared by treating a ketazine or aldazine with a metal halide of the formula MX2 where M is cobalt or nickel and X is a halogen at a temperature of 10* to 300* C.

CYCLIZATION OF AN AZINE Christian H. Stapler, Newtown; Richard W. DAndrea, New Hope, both of Pa.

Inventors:

Assignee:

Filed:

Appl. No.:

US. Cl. ..260/310 D, 260/3 13. l 260/3 19. l

260/566 B Int. Cl. ..C07d 49/10 Field of Search ..260/3 10 D References Cited FOREIGN PATENTS OR APPLICATIONS 2/ 1968 Switzerland ..260/3 10 D United States Patent [151 3,666,772 Stapfer et al. 1 May 30, 1972 PREPARATION OF PYRAZOLINES BY OTHER PUBLICATIONS Chaco et al. J. Org. Chem. Vol. 27, pages 2,765- 7 (1962). QD241J6 Curtius et al. Berichte Vol. 27, pages 770- 3 1894). 0D] .D4 Elderfield Heterocyclic Compounds Vol. 5, pages 88- 9 N .Y., Wiley, 1957. QD400.E4

Kishner Chemisehes Zentralblatt Vol. 83, 1, pages 2025- 6(1912).QD1.C7

Kost et a1. Chem. Abst. Vol. 51, Columns 1943- 4 (1957). QDLASI Wiley et al. Pyrazoles, Pyrazolines, Pyrazolidines, lndazoles and Condensed Rings Page 192 N.Y., Interscience, 1967 QD401.W5p

Primary Examiner-Natalie Trousof Attorney-Cushman, Darby & Cushman [57] ABSTRACT Alkyl substituted pyrroles and pyrazolines are prepared by treating a ketazine or aldazine with a metal halide of the formula MX, where M is cobalt or nickel and X is a halogen at a temperature of 10 to 300 C.

5 Claims, No Drawings preparation of alkyl the present invention will become apparent from the detailed description given hereinafter; it should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

It has now been found that these objects can be attained by l treating an azine of the formula where R and R, are hydrogen or lower alkyl, e.g., alkyl of one to four carbon with a catalytic amount of a metal halide of the formula MX where M is cobalt or nickel and X is a halogen to form a 2-pyrazoline of the formula CH: H

or (2) treating an azine of the formula where R, and R are hydrogen or lower alkyl of two or more, e.g., four or five carbon atoms and R, and R are lower alkyl, e.g., one to four carbon atoms or R together with R.CH, form a ring with six methylene units and/or R, together with R,CH, forms a ring with six methylene units with a catalytic amount of a metal halide of the formula MX, with elimination of one mole of ammonia to form a substituted pyrrole of the formula R R7 1 10 [R10 N .7 fivw is. V, .7,

where R, and R are lower alkyl, e.g., of one to four carbon atoms and R and R are hydrogen or lower alkyl of at least two carbon atoms, e.g., two or four carbon atoms or R together with R forms a ring with six methylene units and/or R, together with R forms a ring with six methylene units.

Both reactions (1) and (2) can be carried out over a wide range of temperatures, e.g., 10 to 300 C, preferably 20 to 200 C.

As the catalyst Mx these canbe used: CoCl CoBr NiCl NiBr,, NiF, or Nil As the starting azine. these can be used acetaldazine, propionaldazine, butyraldazine, isobutyraldazine, valeral dazine, acetone azine, methyl ethylketazine, diethyl ketazine (3-pentanone azine), methyl propyl ketazine, methyl butyl ketazine, dibutyl ketazine, dipropyl ketazine, ethyl butyl ketazine, ethyl, -propyl ketazine, propyl butyl ketazine, cyclohexanoneazin'e.

The cobalt and nickel halide catalystsare generally used in an amount of 0.001 to 5 parts per 100 pans by weight of azine. However, .the proportion is not critical, e.g., the azine can be passed over the supported catalyst so that 10, 50 or more parts of catalyst are presentper part of azine, although the use of such larg'e-amounts of catalyst is not the most economical method of operation.

Examples of compounds which can be prepared according to the present invention are 3,5,S-trimethyl-Z-pyrazoline, 5- methyl-Z-pyrazoline, 3,5-diethyl-5-methyl-Z-pyrazoline, 3,5- dibutyl-5-methyl-2-pyrazoline, 3-butyl-5-methyl-pyrazoline, 3-butyl-S-propyl-5-methyl-2-pyrazoline, 3-isopropyl-5- methyl-Z-pyrazoline, 3-ethyl-5-methyl-2-pyrazoline, 3,5- dimethyl-Z-pyrazoline, 3,4-dimethyl pyrrole, 2,5-diethyl-3,4- dimethyl pyrrole, octahydrocarbazole, 2,3,4,5-tetraethyl pyrrole, 2,5-dibutyl-3,5-dimethyl pyrrole, 2-propyl 3,4-diethyl pyrrole, 3,4-di(isopropyl) pyrrole, 2,5-diethyl-3,4 dibutyl pyrrole.

In general, the yields of pyrazolines are higher than the yields of pyrrole. This is apparently due to the fact that in the reaction to form the pyrrole the pyrrole ammonia is eliminated quantitatively and the hydrogen abstraction which takes place isaccompanied by the formation of polymeric materials which reduces the yields.

It has further been observed that whenever both a methyl and a methylene, group are concurrently adjacent to the nitrogen bonded carbon atoms, as in the case of methyl ethyl ketazine (Z-butanone azine), the methyl group prevails and the intermediate transition metal complex formed favors the formation of a pyrazoline.

Unless otherwise indicated, all weight.

C01,, COB,

parts and percentages are by EXAMPLE I 0.5 g of anhydrous cobalt (ll) chloride was added to 112 g of acetone azine and the reaction mixture was kept at reflux for 24 hours. Upon fractional distillation 86 g (77 percent yield) of pure 3,5,S-trimethyl-2-pyrazoline was isolated. This compound was characterized by its physical constants m.p. -8 C; bp l56-l60C.

Calculated for C H N,

C=64.28%; H= 10.80%; N =25.00% Found:

C=64.32%; H= l0.75%; N= 24.95%

EXAMPLE 2 Eighty-four grams of acetaldazine was refluxed for [2 hours in presence of QM g of nickel (ll) chloride and after fractional distillation, 42 g (50 percent yield) of 5-methyl-2- pyrazoline hp 73 C. The picrate of the pyrazoline had a MP. of l27C.

The pyrazoline compound was identical toa sample of 5- methyl-Z-pyrazoline prepared by other known synthetic routes.

EXAMPLE 3 A mixture of M0 g of methylethyl ketazine and l g of cobalt (ll) bromide was refluxed for 24 hours according to the general procedure of the preceeding examples. After the usual distillation under vacuum, 88.6 g (63 percent yield) of pure 3,5-diethyl-S-methyl-Z-pyrazoline boiling at l-200 C1760 mm Hg was obtained.

Calculated for C l-I N,

C=68.6%; H= l 1.4%; N=20.0%

Found:

C 69.0%; H= l 1.4%; N= 19.7%

EXAMPLE 4 Found:

C= 8| .88%; H 9.69%; N 7.99%. What is claimed is: 1. A process for the cyclizatlon of an aldazine or ketazine of 0.5 g of anhydrous cobalt (II) iodide was added to a solution 5 the formula of 168 g of 3-pentanone azine in 250 ml of o-xylene and the reaction mixture was refluxed for 24 hours. The xylene was evaporated and the residue distilled under high vacuum. Seventy-five grams (50 percent yield) of 3,4-dimethyl-2,5 diethyl pyrrole bp 155 C was isolated. The yellow oil, discoloring rapidly in air, was characterized by elemental analysis and nuclear magnetic resonance.

Calculated for C l-l N C 79.53%;1-1 =11.32%;N 9.27% Found:

C= 79.50%; H= 1 1.29% N= 9.29%

EXAMPLE 5 The general procedure of Example 4 was adopted for the preparation of 49 g (46 percent yield) of 3,4-dimethyl pyrrole from 1 12 g of propional azine and 1.0 g of nickel (ll) bromide. bp 192 C.

EXAMPLE 6 where R, and R, are hydrogen or lower alkyl to form an alkyl Z-pyrazoline of the formula CH; II

comprising treating the azine with a metal halide of the formula, MX where M is cobalt or nickel and X is a halogen, the MX is used in an amount of at least 0.001 part per parts of aa'ne and the reaction is carried out at a temperature of 10 to 300 C.

2. A process according to claim 1 wherein R and R are both methyl.

3. A process according to claim 2 wherein the M,x is used in an amount of from 0.001 up to 50 parts per part of azine.

4. A process according to claim 1 wherein X is chlorine, bromine or iodine.

5. A process according to claim 1 wherein R, and R are both ethyl. 

2. A process according to claim 1 wherein R1 and R2 are both methyl.
 3. A process according to claim 2 wherein the MeX2 is used in an amount of from 0.001 up to 50 parts per part of azine.
 4. A process according to claim 1 wherein X is chlorine, bromine or iodine.
 5. A process according to claim 1 wherein R1 and R2 are both ethyl. 